Specific immunotherapy with standardized extracts can induce systemic reactions (SRs), possibly increased by a rush immunotherapy (RIT) protocol. A prospective study in 1152 mite-allergic patients (3 to 63 years of age) examined the incidence of SRs during an RIT or a step protocol. All patients received the same standardized extract of Dermatophagoides pteronyssinus with the same maintenance dose. In the first group, 290 patients had an RIT protocol without any preventive measure. In a second group, the prevention of SRs during RIT was attempted by pretreating 160 patients with methylprednisolone (0.5 mg/kg/day), ketotifen (2 mg/day), and theophylline (10 mg/kg/day). In a third group (479 patients), the same pretreatment was associated with preventive measures and with FEV1 results and the occurrence of large local reactions. A fourth group consisted of 223 patients who received a step protocol with the same pretreatment and preventive measures. The incidence of SRs per patient was 36.2% with RIT alone, 16.2% when the pretreatment was added, and 7.2% when pretreatment and preventive measures were used. Patients receiving the step protocol had 5.4% SRs. Adrenaline had to be used from 10.0%, 4.6%, 0.2%, and 0.2%, respectively. No reaction started 45 minutes or later after the last injection. Children younger than 5 years of age had a significantly greater number of SR.